B. Chabance et al. (Biochimie 80, 155-165, 1998) have shown that after eating, many peptides derived from α-, β- or κ-caseins, including CGMP, can be detected in stomach and blood, thus indicating that these peptides can cross the intestinal barrier.
Diabetes mellitus is a metabolic disorder characterized by the failure of body tissues to store carbohydrates at the normal rate. Resistance to the action of insulin is the most important factor to type II diabetes. When this resistance exceeds the capacity of the beta cells to produce insulin, a person becomes diabetic. During the last 70 years people suffering from diabetes have been greatly aided by receiving controlled amounts of insulin.
Historically, insulin has been administered by injection to combat diabetes. Administering an injection requires expertise, and compared to oral administration, injecting a medicament is not as safe, convenient or acceptable to the patient. In light of these concerns, it is clear that there is a need for new nutritional or therapeutic products that may be administered orally.
Proglucagon, synthesized by L-cells found in the distal ileum and colon, is known to be post-translationally processed into peptides including glucagon-like peptide-1 (GLP-1), a potent insulin secretagogue. In addition to potentiating glucose-induced insulin secretion, GLP-1 is known to stimulate proinsulin gene expression and proinsulin biosynthesis.
Other actions of GLP-1 include the inhibition of glucagon secretion and gastric motility. GLP-1 can bind in the brain, promoting satiety and suppressing food intake. Increasing insulin secretion is a key goal in the treatment of type II diabetes and stimulation of endogenous release of GLP-1 is a potential/prospective alternative to intravenous administration.
Improving glucose control in diabetes can provide the advantage of reducing the associated risks of hyperglycemia, including blindness, limb amputations, kidney failure and cardiovascular disorders.
A number of in vitro cell models of animal origin have been developed to study the regulation of GLP-1 secretion including a fetal rat intestinal cell culture, an isolated canine L cell, a secretin tumor cell (STC-1) cell line, and the GLUTag enteroendocrine cell line. While these models have provided useful information regarding the factors which regulate GLP-1 secretion and proglucagon expression, they suffer from the problem that they do not necessarily represent the same regulators and mechanisms which are active and occur in human L cells.
The present invention addresses the problems set out above.